GENITOURINARY MALIGNANCIES (GU) RESEARCH PROGRAM PROJECT SUMMARY/ABSTRACT The Genitourinary Malignancies (GU) Research Program explores fundamental biologic pathways of critical importance to the development and progression of prostate, renal and bladder cancer, and fosters translational, investigator-initiated clinical trials to advance therapeutic options for patients with GU malignancies. The overarching goals of the GU Program are to identify core mechanistic pathways that mediate the development and progression of prostate, renal, and bladder cancers and to translate such information to inform and conduct investigator-initiated clinical trials (IITs) that improve patient outcomes. The program is organized around 3 scientific aims: (1) Discover mechanisms of response and resistance to existing and emerging therapies for prostate and renal cancer, (2) Develop novel biomarkers for early detection, prognosis, therapeutic and clinical outcomes across GU malignancies, and (3) Ascertain the immunomodulatory environment of renal cell carcinoma and bladder cancer and develop novel immunotherapeutic clinical trials. The aims and the disease-focused nature of the GU Program allow for multi- disciplinary investigations that are highly mechanistic, translational, and clinically focused. These aims reflect major working groups and initiatives that coalesces program members with other cancer center investigators through inter-programmatic collaborations that result in preclinical and clinical research efforts, grants, and trial protocols. Extensive use of Case CCC shared resources, specifically, Biostatistics, Cytometry, Imaging, Athymic, and Translational Research facilitate all aspects of member discoveries. Under the leadership of Brian Rini (Clinical Co-Leader) and Nima Sharifi (Co-Leader) the GU Program has 28 members including 14 full, 3 associate, and 11 clinical members. Members represent 13 departments, giving rise to a total of $4.6M in research grant funding (annual direct costs), of which $3M is peer-reviewed and $1.7M is NCI-funded. Between 2012 and 2016, GU program members published 802 publications. Cancer and Program related publications included 20% inter-programmatic, 25% intra-programmatic, 8% inter- and intra- programmatic and 10% that involved collaborations with another Cancer Center. This highly effective program has made major practice-changing contributions benefiting cancer patients. Examples include: 1) the discovery of an abiraterone metabolite, (D4A), a potent androgen receptor inhibitor, leading to clinical studies; 2) identification of a 17-gene expression that predicts prostate cancer aggressiveness especially for intermediate Gleason score tumors that has been incorporated into NCCN guidelines for treatment decisions; 3) the identification of the role of myeloid-derived suppressor cells (MDSCs), PD-L1 and MEK induction in In renal cancers treated with sunitinib leading to Phase III trials; and 4) the discovery of a gain-of-function missense in 3?-hydroxysteroid dehydrogenase-1 (3?HSD1; (HSD3B1)) leading to multiple confirmatory studies indicating worse outcomes in men carrying the polymorphism.